Abstract Cerebellar ataxias, a group of disabling and untreatable neurodegenerative disorders affecting up to 150,000 people in the United States, result in uncoordinated limb and trunk movements and falls, frequently leading to wheelchair confinement. At the cellular level, the ataxias are primarily associated with neuronal loss within the cerebellum and its associated pathways. Neuronal dysfunction precedes and accompanies neuronal loss and contributes to motor symptoms, but the mechanisms responsible for these early events are poorly understood. In Spinocerebellar Ataxia type 1 (SCA1), the best studied and one of the more common dominantly inherited ataxias, a reduction in cerebellar Purkinje neuron cell size and dendritic arborization precedes overt neuronal loss, as in other ataxias. Building on our prior work establishing that electrophysiological dysfunction of cerebellar neurons contributes to motor deficits in different mouse models of ataxia, we now seek to determine whether changes in Purkinje neuron function contribute to altered morphology and motor dysfunction in SCA1. Purkinje neurons generate autonomous, pacemaker action potentials even in the absence of synaptic input. Our preliminary data in a mouse model of SCA1 demonstrate that Purkinje neuron pacemaker firing is initially normal, but by 5 weeks of age, pacemaker firing is disrupted, together with abnormal depolarization of membrane potential associated with reduced activity of subthreshold-activated potassium channels. Strikingly, subsequent Purkinje cell shrinkage is associated with relative restoration of pacemaker firing, indicating that cell shrinkage may reflect the attempt of Purkinje neurons to compensate for physiologic dysfunction. We hypothesize that abnormal activity of subthreshold-activated potassium channels is a critical early event in the pathogenesis of SCA1. We also hypothesize that compensatory mechanisms to maintain normal Purkinje pacemaker firing contribute to cell shrinkage - which is actually beneficial - but that failure of this compensation leads to neurodegeneration. In the following specific aims we propose to test these hypotheses at the cell and circuit level, and to explore whether preventing potassium channel dysfunction will ameliorate neurodegeneration and motor dysfunction. The project has three aims. Aim 1 will determine the mechanism underlying membrane depolarization in SCA1 Purkinje neurons. Aim 2 will determine the consequences of Purkinje neuron atrophy on cerebellar circuitry, and aim 3 will determine whether maintaining normal membrane potential will prevent Purkinje neuron atrophy and improve motor symptoms in SCA1 transgenic mice.